Bleeding Emergencies in

Inherited Coagulation Disorders

Giancarlo Castaman

Department of Cell Therapy and Hematology,

San Bortolo Hospital, Vicenza, Italy

44° Congresso Società Italiana di Ematologia Verona, 20-23 Ottobre 2013

Hemorrhagic emergencies 1.  Bleeding potentially life-threatening or

dangerous for function integrity

2.  Clinical and laboratory situation with high risk of potential life-threatening bleeding (hemostatic emergency)

Both with the characteristics of «sudden and unexpected»

Causes of bleeding •  Clotting abnormality:

• Congenital

• Acquired

•  Quantitative/qualitative platelet defects

•  Acquired hemostatic defects

•  Trauma or surgery

Secondary to other disorder(s)

Apparently idiopathic

activation F = factor a = active

TF = tissue factor PL = phospholipids XL = cross-linked

FDP = fibrin degradation products

PL, Ca2+

FXI FXIIa

FXIa Ca2+

FIX

FIXa

FVIIa

FVII

PL, Ca2+

FVIIIa

TF FX

FXa FVa

Prohtrombin

Thrombin

FV

FVIII

Fibrinogen

FXIII

FXIIIa Fibrin monomers Fibrin XL

XL-FDP

Coagulation process

Hemophilia

Rare bleeding disorders

Hemorrhagic emergencies in iniherited coagulation disorders

1.  Apparently primitive in a subject with a bleeding disorder not diagnosed yet

2.  Spontaneous in a patient previously diagnosed with an inherited bleeding disorder

3.  Triggered by trauma or surgery

4.  Inhibitor(s)

Hemorrhagic emergencies in inherited coagulation disorders

1.  Apparently primitive in a subject with a bleeding disorder not diagnosed

2.  Spontaneous in a patient previously diagnosed with an inherited bleeding disorder

3.  Triggered by trauma or surgery

Apparently primitive in a subject with a bleeding disorder not diagnosed

•  Neonatal cerebral bleeding (FXIII> afibrinogenemia> FVII> severe

hemophilia) •  Umbilical stump bleeding (FXIII> afibrinogenemia > FX)

Bleeding symptoms in FX deficiency compared to severe Hemophilia A

Uprichard et al, Blood reviews 2002

Rare Bleeding Disorders: the peculiarity of Afibrinogenemia and

FXIII deficiency

Symptom Afibrinogenemia FXIII deficiency

Severe Hemophilia

Bleeding from umbilical stump

50 % 73 % < 1 %

Spontaneous cerebral bleeding

10 % 30 % ̃ 10%

Factor half-life ̃ 4 days ̃ 14 days 12 hours

FVII deficiency: Bleeding symptoms (IF7 Database)

•  More frequent bleeding –  Menorrhagia 62.9 % –  Epistaxis 60.9 % –  Ecchymosis 45.4 % –  Gum bleeding 30.2 % –  Hemartrosis 18.4 % –  G.I. bleeding 14 % –  Cerebral bleeding 5.7% –  Hematuria 8.2% –  Post-surgery 23.8 %*

* Prevalence in patients undergone surgery

Screening tests for a (severe) bleeding disorder

•  APTT •  PT •  Platelet count •  (PFA©-100 ADP/EPI)

It still happens…

•  Male, born at another hospital , APGAR 10 •  On 12th day, at home, bleeding from umbilical stump

•  Large subcutaneous hematoma right arm from previous venipuncture. Hb 14.2 g/dL, PT, PTT and platelet count normal, sutured at the same hospital

•  The day after, new admission because recurrence of

bleeding from umbilical stump

At the end he arrives…

•  Hb 9.6 g/dL, surgical necrosectomy, transfused with RBC (Hb 7.2 g/dL)

•  Afterwards, large bruising from minor trauma •  When 14 month-old, trauma to upper right incisive

with recurrent oozing for at least 4 days •  Admission at Pediatric Department of our hospital

on pediatrician’s request

Do we need Hemophilia centers ? •  No bleeding history in the family

•  Monochloroacetic acid 1 % = positive (clot lysis < 10 min); 30 min from blood drawing

•  FXIII < 1 U/dL

•  FXIII A gene = 4 bp homozygous deletion in exon 11 (c. 1392-1395 delAATT)

•  Unrelated parents heterozygous

Half-life FXIII ∼ 14 days Levels 2 – 4% sufficient to

prevent spontaneous bleeding

FXIII concentrate ≅ 10-20 U/Kg/ 4 weeks

Outcome

•  Infusion of 500 U FXIII concentrate, bleeding immediately stopped

•  Prophylaxis with 15-20 U/kg FXIII every 4 weeks

•  No further bleeding episodes

Screening tests for Rare Bleeding disorders

Factor PTT PT Fibrinogen ↑↑↑ ↑↑↑ FII ↑↑↑ ↑↑↑ FV ↑↑ ↑↑ FVIII-FIX ↑↑ N FX ↑↑ ↑↑ FXI ↑↑ o ↑↑↑ N FVII N ↑↑ FXII ↑↑↑ N FXIII# N N

# A specific screening test required (Urea 4 M or monochloroacetic acid 1 %)

Hemorrhagic emergencies in inherited coagulation disorders

1. Apparently primitive in a subject with a bleeding

disorder not diagnosed

2. Spontaneous in a patient previously diagnosed with an inherited bleeding disorder

3. Triggered by trauma or surgery

Clinical features of Rare Bleeding disorders: spontaneity of symptoms

•  ∼5 - 10 % of severe Hemophilia patients may suffer from cerebral bleeding, even apparently spontaneous

Severe bleeding in hemophilia

Clinical features of Rare Bleeding disorders:

spontaneity of symptoms Ileopsoas hematoma in hemophilia

• Femoral nerve palsy • Acute compartment syndrome

Clinical features of Rare Bleeding disorders:

spontaneity of symptoms •  3 year-old kid with severe hemophilia A,

tonsillitis and fever 39°5 C •  Recovery after 3 days with antibiotics, no fever,

but pale and letargic

•  Hb 5.7 g/dL; continuous oozing from right tonsil

Occult throat bleeding/hematoma

Piastrina

Deficit di attività procoagulante

• Procoagulant surface

Disordini ereditari della funzione piastrinica (Storage pool, Difetti di secrezione)

GP IIb-IIIa

Piastrina

Disordini ereditari dell’interazione piastrine-parete vascolare e della funzione piastrinica

GP Ib

M. Von Willebrand

Sindrome di Bernard-Soulier Trombastenia di

Glanzmann

Bleeding symptoms (%) in Italian patients with von Willebrand disease

Symptoms

Italian Registry Willebrand

(n = 896) Type 1 Type 2 Type 3

Epistaxis 63 65 67

Gum bleeding 33 39 56

Easy Bruising 38 46 56

Menorrhagia 34 36 65

Muscle hematoma 14 15 33

Gastrointestinal bleeding 6 16 20

Hemarthrosis 3 4 46

Hematuria 2 5 12

Cerebral bleeding 0.1 2 9

Federici et al, 2005

Augusta 74 y

Klas Oskar 78 y

Lars-Uwe 1 y

Harald 44 y

Anna 4 y

Thomas 31 y

Sylvia 41 y

Dagny 2 y

Runar 40 y

Hjördis 13 y

Greta 5 y

Gerda 34 y

Lars 29 y

Dagny 2y

† † † † † † †

Roger 13 y

Helga 17 y

Viking 10 y

Robert 17 y

Cecilia 10 y

Birgitta15 y

Tage 9 y

Jan Uluf 1 y

Anders 8 y

Monika 4 y

Börje 6 y

Severe bleeding Mild or trivial bleeding

Family S, Föglö Island

TYPE 3 VWD (IVS46 +1, G>T n.7770+1)

FVIII:C 160 IU/dL VWF:Ag 98 IU/dL

FVIII:C 72 IU/dL VWF:Ag 82 IU/dL

FVIII:C 86 IU/dL VWF:Ag 30 IU/dL

FVIII:C 131 IU/dL VWF:Ag 140 IU/dL

FVIII:C 121 IU/dL VWF:Ag 99 IU/dL

FVIII:C 90 IU/dL VWF:Ag 45 IU/dL

FVIII:C 1.2 IU/dL VWF:Ag 1.8 IU/dL

FVIII:C 61 IU/dL VWF:Ag 35 IU/dL

FVIII:C 57 IU/dL VWF:Ag 63 IU/dL

IVS 46 +1 G>T

Bleeding at menarche in severe von Willebrand disease women

•  Severe bleeding at menarche age 13, 24 hour after starting admitted with Hb 5.2 g/dL, still bleeding

•  Treated with RBC, antifibrinolytics, FVIII/VWF concentrates

Menorrhagia Score O

no or trivial 1

present

2 consultation/

pill use/ iron therapy

3 transfusion/

hysterectomy/ curettage/

replacement therapy

Type 1 VWD (n= 54)

16 (29.6 %)

10 (18.5 %)

16 (29.6 %)

12 (22.3 %)

Controls (n = 121)

101 (83.5 %)

3 (2.5 %)

9 (7.5 %)

8 (6.5 %)

IMS, JTH 2005

Sex and number

Mean RBC

(Units)

Total RBC

(Units)

Platelet concentrates (Total Units)

Males (n = 8) 5.8 46 12

Females (n = 12)@ 19.2 230 163

Influence of sex on bleeding tendency and transfusion requirement in Glanzmann

Thrombasthenia (modified from Awidi, Am J Hematol 40, 1, 1992)

20 patients; mean follow-up 5.6 years (1 – 8.5; 140 pt/years)

@ Menorrhagia: 8 pts: 140 U RBC + 80 PC

Gastrointestinal bleeding in von Willebrand disease

•  Often elder, severe phenotype and/or lack of high molecular weight VWF multimers (Fressinaud, 1993; Castaman, 2012) •  Acquired (aortic valve stenosis, AVWS) •  Angiodysplasia over GI tract, often of difficult localization by diagnostic techniques

•  High requirement for blood transfusion, treatment cumbersome (prophylaxis and high FVIII/VWF concentrate requirement, octreotide, talidomide, atorvastatin…)

Number and types of bleeding episodes in VWD during 24-month follow-up

Castaman et al, 2011; 2012

Type 1 R1205H (n = 60)

Type 1 C1130F (n = 23)

Type 2 A (n = 46)

Type 2 M (n = 61)

Epistaxis 2 0 19 20

Menorrhagia 2 6 18 11

Retroperitoneal 0 1 0 0

Oral 0 0 4 4

Hemorrhoidal 0 0 1 4

Gastrointestinal 1 0 53 7

Hematuria 0 0 0 3

Hemorrhagic emergencies in iniherited coagulation disorders

1.  Apparently primitive in a subject with a bleeding disorder not diagnosed

2.  Spontaneous in a patient previously diagnosed with an inherited bleeding disorder

3.  Triggered by trauma or surgery

Hemorrhagic emergencies triggered by trauma or surgery

•  In patients already diagnosed: - Inadequate anti-hemorrhagic prophylaxis - Anatomical reasons •  In patients with mild inherited bleeding disorder

still undiagnosed and manifest after surgery or trauma (e.g., mild hemophilia)

Inhibitors in hemophilia •  IgG inhibiting clotting activity of FVIII/FIX •  Usually < 20 exposure days to concentrate, rare

later

•  ∼ 25 % severe hemophilia A patients, <5% severe hemophilia B (risk of severe allergic reactions)

•  Often transient, sometimes occurring during hemostatic challenges (e.g. surgery)

Tretament at very early age

Intensive treatment Concurrent disorders (immunity) ? Type of concentrate (+/- VWF)

Precocious prophylaxis

«Null» gene mutations/

major deletions Expression of genes involved in immune

response

Risk of inhibitor

Cumulative inhibitor incidence in 1112 nonsevere hemophiliaA patients, according to cumulative exposure days to factor VIII concentrates

Eckhardt C L et al. Blood 2013

MILD SEVERE

•  Inhibitor occurs in ~10 % of non-severe Hemophilia A, often after intensive treatment •  Risk increases continuosly with increasing

exposure days

Distribution of F8 missense mutations associated with inhibitor development

Eckhardt C L et al. Blood 2013

•  Genotyping advised at diagnosis also in mild hemophilia A

•  Use desmopressin

Hemophilia B and inhibitors in Italy

Mutation ED at inhibitor onset

Peak (BU)

ANA Immunotolerance

Trp194Stop 15 140 NO NO Trp194Stop 8 90 NO YES, after 1,598 ED with

rFIX Arg248Stop 30 2.6 NO YES, after 26 ED with pdFIX

Arg248Stop 8 1.6 YES NO, by-passing agents Arg252Stop 14 117 NO YES, after 153 ED with rFIX

Arg252Stop >20 11 NO YES, partial response with rFIX, still ongoing

Deletion exons A-H >30 25 YES NO Deletion exons A-H 4 1.7 YES NO, by-passing agents Deletion complete 50 18 NO On demand treatment Deletion complete 31 6.4 NO NO, by-passing agents

Castaman et al, 2013

Patient with exons A-H deletion

•  6 yr-old boy with FIX < 1 U/dL; no treatment before the age of 5

•  April 2010 – Large left thigh hematoma: Benefix 1000 U/day for 3 days

•  End of May: Inhibitor BU 0

•  June 18: Left knee hemarthrosis: Benefix 1000 U -  June 29: BU 1.7, recurrence of hemarthrosis -  New treatment with rFIX in intensive care unit -  After ~200 U, infusion discontinued because of:

•  Acute asthma with respiratory failure •  Tongue and lips edema •  Tachycardia •  Peripheral cianosis •  Epinephrine and hydrocortisone

High Responding / Low Responding Inhibitors

•  High responding: >5 Bethesda Units (BU) - FVIII/IX concentrates inefficacious - Every treatment induces an increase of BU titer

(anamnestic response) •  Low Responding: - Trues: < 5 BU even after reexposure to concentrate - Transient: < 5 UB disappears continuing treatment within 6 - 12 months

Can be treated with FVIII/IX by increasing the dose

(neutralising dose)

Recommendations for the treatment of hemophilia with inhibitors (BU > 5)

Treatment or prophylaxis (invasive procedures, surgery) Firstline with by-passing agents: •  rFVII 90 µg/Kg every 2-3 hr until bleeding stops or

persistence of hemorrhagic risk. Partial or complete response 75-100%.

Thrombotic complications <1:10.000 infusions •  aPCC 50-100 UI/Kg every 8-12 hr up to max 200 U/kg/day.

Partial or complete response 85-100%. Thrombotic complications 4-8:100.000 infusions Duration based on clinical ground, without specific laboratory

monitoring

Treatment of hemarthrosis as emergency situation to

minimize the disability of long-term hemophilic arthropathy

What happens with hemarthrosis: Hemophilic arthropathy

Normal joint

Chronic crippling artropathy

Prompt and adequate treatment of hemarthrosis to minimize the disability of

long-term hemophilic arthropathy

• Quantity: Adequate dose of factor concentrate (≥ 25 U/Kg)

•  Timely: Home-Treatment •  Prevention/rehabilitation: Prophylaxis

Conclusions •  The management of patients with inherited bleeding

disorders should foresee the risk of emergency bleeding

•  Regular surveillance allows the identification of at-risk patients (e.g., inhibitor development)

•  Surgery should be always coordinated with hemostasis staff to plan treatment for unexpected bleeding

•  Treatment of hemarthrosis requires adequate dosage and should be timely to minimize long-term disabilities

•  Prophylaxis is the gold-standard for children

What happens with hemarthrosis

Early

Late

Normal joint